• Johns Hopkins and affiliated
institutions in Maryland have a total
economic impact of nearly $10 billion
in fiscal year 2010.

in 16 patients are living five years after diagnosis ( 3). Jill Ward,
who is about to celebrate her fifth year of survivorship, is a rarity.
Much more work needs to be done if the outlook for those
diagnosed with this disease is to improve. For some time,
researchers have known the identity of a predominant cancer-driving molecular defect, but they have been unable to successfully
develop drugs that precisely target it. They are actively looking for
ways around this obstacle. One approach that basic research
suggests might have promise is combining two molecularly
targeted drugs that are specific for different signaling network
components ( 98), and this idea is currently in the early stages of
being tested in clinical studies.

Combinations of molecularly targeted drugs are also being
investigated as potential new approaches to treating cancers other
than pancreatic cancer. For example, a drug that blocks the
mutated B-RAF protein, which is the molecular defect found to
drive more than 50% of melanoma cases, has revolutionized the
treatment of this deadly disease ( 99); however, these cancers
eventually acquire resistance to the drug and they progress (see
Fig. 16, p. 50 and Sidebar on Drug Resistance, p. 49). Melanoma
research has identified several molecular pathways that bypass the
inhibition of mutated B-RAF, and recently initiated clinical studies
are assessing whether adding a second drug that precisely targets
one of these resistance signaling networks will further prolong
survival in patients who have experienced progression. The results
are eagerly awaited.

In 2011, the Nobel Prize in Physiology
or Medicine was awarded for research
discoveries that furthered the
understanding of the immune system
and influenced immunotherapy for
treating cancer.

A New Day for Immunotherapy

Over the past four-plus decades, cancer researchers have
accumulated a tremendous understanding of the complexity of
cancer. It is now evident that while the genetic alterations in cancer
cells have a profound effect on the development of cancer, cancer
cells can also modify their surroundings, often called the tumor
microenvironment, enhancing the growth and spread of the cancer.

A key component of the tumor microenvironment is the immune
system. Research has determined that in some cases, the immune
system completely eliminates a cancer before it becomes clinically
apparent. This fact is central to the idea that it might be possible to
develop therapies that train a patient’s immune system to destroy a
cancer. Putting this into clinical practice, however, has proven
extremely challenging. Recent scientific advances have revealed
one of the reasons for this phenomenon is that tumors have
developed many sophisticated ways to block their own destruction
by the immune system. Progress in our understanding of the
approaches that tumors use to escape elimination is finally
converging with advances in our basic understanding of the
immune system to yield multiple new strategies that have the
potential to revolutionize cancer treatment.

Cancer treatment that employs the body’s own immune system
against cancer is called immunotherapy. Not all immunotherapies
operate in the same way, however, and the ongoing discovery of the
many intricacies of the immune system is continuing to open new
pathways to the development of novel treatment strategies. Among
the immunotherapy approaches currently saving patient lives are
some that seek to boost the natural cancer-fighting ability of the
immune system by taking its brakes off, some that enhance the
killing power of the patient’s own immune cells and others that flag
cancer cells for destruction by the immune system. The first
approach—using therapies that boost the immune system by taking
its brakes off—is now leading the field of immunotherapy, producing
remarkable and durable responses in cancers that are not amenable
to standard treatments. However, other approaches are starting to
gain traction as well after many challenging years of development.

Targeting the Immune System to Release Its Brakes

It is well established that immune cells called T cells are naturally
capable of destroying cancer cells and that this ability can be
suppressed by the tumor. One explanation for this was provided by
the discovery that T cells in the tissues surrounding a tumor
express high levels of molecules that tell T cells to slow down and
to stop acting aggressively (see Fig. 18, p. 62). This finding led
researchers to seek ways to counteract these molecules, which are
often called immune checkpoint proteins.

The most well-understood immune checkpoint protein is called
CTLA- 4, and a therapeutic antibody, ipilimumab (Yervoy), which
targets CTLA- 4, was approved by the FDA in March 2011 for the